trovafloxacin

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2014/02/26 07:58:30」(JST)

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Trovafloxacin

Systematic (IUPAC) name
7-(6-Amino-3-azabicyclo[3.1.0]hex-3-yl)-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-[1,8] naphthyridine-3-carboxylic acid
Clinical data
AHFS/Drugs.com	Micromedex Detailed Consumer Information
MedlinePlus	a605016
Legal status	Withdrawn from market
Routes	Oral, intravenous
Identifiers
CAS number	147059-72-1 Y
ATC code	J01MA13
PubChem	CID 62959
DrugBank	DB00685
ChemSpider	16736478 Y
UNII	9F388J00UK Y
KEGG	D08654 Y
ChEMBL	CHEMBL428 Y
Chemical data
Formula	C20H15F3N4O3
Mol. mass	416.353 g/mol
SMILES O=C(O)C2=CN(c1nc(c(F)cc1C2=O)N3C[C@H]4[C@H](N)[C@H]4C3)c5ccc(F)cc5F
InChI InChI=1S/C20H15F3N4O3/c21-8-1-2-15(13(22)3-8)27-7-12(20(29)30)17(28)9-4-14(23)19(25-18(9)27)26-5-10-11(6-26)16(10)24/h1-4,7,10-11,16H,5-6,24H2,(H,29,30)/t10-,11+,16+ Y Key:WVPSKSLAZQPAKQ-CDMJZVDBSA-N Y
Y (what is this?)  (verify)

Trovafloxacin (sold as Trovan by Pfizer and Turvel by Laboratorios Almirall) is a broad spectrum antibiotic that inhibits the uncoiling of supercoiled DNA in various bacteria by blocking the activity of DNA gyrase and topoisomerase IV. It was withdrawn from the market due to the risk of hepatotoxicity. It had better gram-positive bacterial coverage and less gram-negative coverage than the previous fluoroquinolones.

Adverse reactions

Trovafloxacin use is significantly restricted due to its high potential for inducing serious, sometimes fatal liver damage.

Controversy

Nigerian clinical trial

Main article: Kano Trovafloxacin trial litigation

In 1996, during a meningitis epidemic in Kano, Nigeria, the then-untested drug was administered to approximately 200 infected children. Eleven children died in the trial: five after taking Trovan and six after taking an older antibiotic used for comparison in the clinical trial. Others suffered blindness, deafness and brain damage, the cause of which is difficult to determine because these disabilities are relatively common outcomes of the disease itself. A panel of medical experts later implicated Pfizer in the incident, concluding the drug had been administered as part of an illegal clinical trial without authorization from the Nigerian government or consent from the children's parents. The case came to light in December 2000 as the result of an investigation by The Washington Post, and sparked significant public outcry. The Nigerian federal government has subsequently sued the drug giant for $8.5bn and Pfizer will face criminal and civil charges brought by the state and federal governments of Nigeria. The most serious error was the falsification and backdating of an ethics approval leader by the lead investigator of the trial, Dr. Abdulhamid Isa Dutse. Dr. Dutse is now the chief medical officer of Aminu Kano Teaching Hospital. The result of the trial was that children treated with oral trovafloxacin had a 5% (5/100) mortality rate compared to a 6% (6/100) mortality rate with intravenous ceftriaxone. This was a non-significant difference.

Between 2002 and 2005 the victims of the Trovan tests in Nigeria filed a series of unsuccessful lawsuits in the United States. However, in January 2009, the United States Court of Appeals for the Second Circuit ruled that the Nigerian victims and their families were entitled to bring suit against Pfizer in the United States under the Alien Tort Statute. A US$75 million settlement with the State of Kano was reached July 30, 2009. The charges filed against Pfizer by Nigeria's federal government, which is still seeking about $6 billion in damages, were not affected by this settlement. Additionally two lawsuits also remain pending in New York, United States. According to Wikileaked US embassy cables, Pfizer's country manager admitted that "Pfizer had hired investigators to uncover corruption links to federal attorney general Michael Aondoakaa to expose him and put pressure on him to drop the federal cases." Boseley, Sarah (9 December 2010). "WikiLeaks cables: Pfizer 'used dirty tricks to avoid clinical trial payout'". The Guardian (London). http://www.guardian.co.uk/business/2010/dec/09/wikileaks-cables-pfizer-nigeria.

Post approval link to hepatotoxicity

When it went on the market in 1998 Trovan became one of Pfizer's top-selling drugs. When first-quarter earnings were announced in April of that year, the company's earnings had increased by 15% over the previous year, with analysts attributing much of that increase to the sales of the "new antibiotic" Trovan. Pfizer had spent hundreds of millions of dollars developing Trovan. In the first year it brought over US$160 million and investors expected it to eventually bring in US$1 billion per year.

In June 1999 the U.S. Food and Drug Administration advised doctors to limit the prescription of Trovan after it had been found "strongly associated" with 14 cases of acute liver failure and six deaths. The FDA had received over 100 reports of liver problems in people taking Trovan, which was at that time being prescribed at a rate of 300,000 patients per month in the United States. Two days later the Committee for Proprietary Medicinal Products recommended to the European Commission that marketing approval of Trovan be suspended for a year.

See also

• Alatrofloxacin, a prodrug of trovafloxacin for intravenous administration
• Adverse effects of fluoroquinolones

References

External links

• Abdullahi v Pfizer. US Court of Appeals 2d Cir 30 Jan 2009

UpToDate Contents

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• 1. フルオロキノロン類 fluoroquinolones
• 2. 成人における市中肺炎の治療に関する抗菌薬の研究 antibiotic studies for the treatment of community acquired pneumonia in adults
• 3. 成人における特定病原体により引き起こされる細菌性髄膜炎の治療 treatment of bacterial meningitis caused by specific pathogens in adults
• 4. 成人における細菌性髄膜炎の初期治療および予後 initial therapy and prognosis of bacterial meningitis in adults
• 5. レジオネラ感染の治療および予防 treatment and prevention of legionella infection

English Journal

• First liquid chromatography method for the simultaneous determination of levofloxacin, pazufloxacin, gatifloxacin, moxifloxacin and trovafloxacin in human plasma.

• Sousa J, Alves G, Campos G, Fortuna A, Falcão A.SourceDepartment of Pharmacology, Faculty of Pharmacy, University of Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal; CNC - Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal.
• Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.J Chromatogr B Analyt Technol Biomed Life Sci.2013 Jul 1;930:104-11. doi: 10.1016/j.jchromb.2013.04.036. Epub 2013 May 4.
• For the first time a simple, selective and sensitive liquid chromatography method was developed and validated for the simultaneous determination of levofloxacin (LEV), pazufloxacin (PAZ), gatifloxacin (GAT), moxifloxacin (MOX) and trovafloxacin (TRO) in human plasma. Samples were pre-treated with ac
• PMID 23727874

• Evaluating the In Vitro Inhibition of UGT1A1, OATP1B1, OATP1B3, MRP2, and BSEP in Predicting Drug-Induced Hyperbilirubinemia.

• Chang JH, Plise E, Cheong J, Ho Q, Lin M.SourceDrug Metabolism and Pharmacokinetics, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
• Molecular pharmaceutics.Mol Pharm.2013 Jun 21. [Epub ahead of print]
• Hyperbilirubinemia may arise due to inadequate clearance of bilirubin from the body. Bilirubin elimination is a multifaceted process consisting of uptake of bilirubin into the hepatocytes facilitated by OATP1B1 and OATP1B3. Once in the hepatocytes, it is extensively glucuronidated by UGT1A1. Eventua
• PMID 23750830

• Implication of hepatic transporters (MDR1 and MRP2) in inflammation-associated idiosyncratic drug-induced hepatotoxicity investigated by microvolume cytometry.

• Saab L, Peluso J, Muller CD, Ubeaud-Sequier G.SourceUMR CNRS 7200, Laboratoire d'Innovation Thérapeutique, Université de Strasbourg, FMTS, Faculté de Pharmacie, Illkirch, France.
• Cytometry. Part A : the journal of the International Society for Analytical Cytology.Cytometry A.2013 Apr;83(4):403-8. doi: 10.1002/cyto.a.22263. Epub 2013 Feb 11.
• Idiosyncratic drug-induced hepatotoxicity accounts for about 13% of all cases of acute liver failure, therefore cited as the most frequent reason for post-marketing drug withdrawal. Despite this, the underlying mechanisms remain poorly understood due to lack in adequate screening assays and predicti
• PMID 23401306

Japanese Journal

• Susceptibility Patterns of Enterococci Causing Infections

• , ,
• The Tohoku Journal of Experimental Medicine 202(1), 23-29, 2004
• … Minimal inhibitory concentrations (MICs) of penicillin G, ampicillin, gentamicin, ciprofloxacin, ofloxacin, levofloxacin, grepafloxacin, trovafloxacin and gemifloxacin were determined by broth microdilution testing method. … Among fluoroquinolones, gemifloxacin and trovafloxacin were the most potent antibiotics tested. …
• NAID 130004821939

• PHARMACOLOGICAL EVALUATION OF GARENOXACIN, A NOVEL DES-F(6)-QUINOLONE ANTIMICROBIAL AGENT : EFFECTS ON THE CENTRAL NERVOUS SYSTEM

• , , [他], ,
• Journal of toxicological sciences 28(1), 35-45, 2003-02-28
• … Garenoxacin injected intracerebroventricularly into mice caused clonic convulsion at a higher dose (50μg/body) than norfloxacin, ciprofloxacin, sitafloxacin and trovafloxacin. …
• NAID 110001802887

• Levofloxacin and trovafloxacin inhibition of experimental fracture healing

• PERRY AC
• Clin Orthop Relat Res. 414, 95-100, 2003
• NAID 30009203030

Related Links

• Trovafloxacin - Wikipedia, the free encyclopedia

Trovafloxacin (sold as Trovan by Pfizer and Turvel by Laboratorios Almirall) is a broad spectrum antibiotic that inhibits the uncoiling of supercoiled DNA in various bacteria by blocking the activity of DNA gyrase and topoisomerase IV. It was ...

• Questions and Answers on Trovafloxacin Public Health Advisory

30 Apr 2009 ... What action is FDA announcing today? FDA is issuing a Public Health Advisory to inform physicians and the public regarding new safety information about Trovan (trovafloxacin/alatrofloxacin), an antibiotic used to treat many ...

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